Pro-inflammatory cytokines play important roles in mediating inflammation and immune responses. Dysregulation of cytokine functions has been implicated in autoimmune diseases, such as arthritis. Cytokines exert their biological functions by activating multiple signaling cascades, including STAT and NF-kB pathways. My long-term research goal is to understand cytokine signaling and immune regulation. We have identified a novel family of proteins named PIAS (protein inhibitor of activated STAT), which negatively regulates STAT signaling. Our recent studies revealed that PIAS1 is also an inhibitor of NF- kB , and that PIAS1 plays an important role in controlling the pro-inflammatory cytokine production in vivo. The overall goal of this proposal is to further study the mechanism and function of PIAS1 in NF-kB signaling, proinflammatory cytokine production and arthritis using combined biochemical and genetic approaches. First, we will study the molecular mechanism of PIAS1-mediated inhibition on NF- kB. We will address the specificity of PIAS1-mediated inhibition on NF- kB -dependent genes. We will examine the importance of SUMO E3 ligase activity of PIAS1 in NF- kB signaling. We will also study the involvement of other PIAS proteins in the regulation of NF- kB . Second, we will address the mechanism of PIAS1-mediated regulation of pro-inflammatory cytokine production. We will study PIAS1-mediated regulation of cytokine production at both transcriptional and posttranslational levels. Third, we will address the in vivo role of PIAS1 in the pathogenesis of arthritis using various animal models. We will examine the possible mechanisms of PIAS1- mediated action in arthritis models. We will also study the involvement of STAT1 signaling in arthritis pathogenesis. These studies will provide further understanding of the role of PIAS1 in inflammation and immune diseases and may identify novel targets for therapeutic interventions.